The present invention, in some embodiments thereof, relates to therapy and, more particularly, but not exclusively, to treatment of undifferentiated cells such as pluripotent cells and undifferentiated cancel cells, to novel compounds suitable therefor, and to methods of identifying compounds suitable therefor.
Human pluripotent stem cells (hPSCs) hold great promise for regenerative medicine, due to their unique abilities to self-renew and to differentiate into all the cell types of the human body. However, the same properties also make these cells potentially tumorigenic.
Tumor formation was reported to positively correlate with the residual presence of undifferentiated pluripotent cells [Miura et al., Nature Biotechnology 27:743-745 (2009)]. Very few hPSCs are required for teratoma formation [Lee et al., Cell Cycle 8:2608-2612 (2009); Hentze et al., Stem Cell Research 2:198-210 (2009)], and even after prolonged differentiation in culture some tumorigenic pluripotent cells remain [Narsinh et al., Journal of Clinical Investigation 121:1217-1221 (2011); Ghosh et al., Cancer Research 71:5030-5039 (2011); Fu et al., Stem Cells and Development 21:521-529 (2012)].
It has therefore been recommended to eliminate residual pluripotent cells prior to the clinical application of their derivatives [Ben-David & Benvenisty, Nature Reviews Cancer 11:268-277 (2011)].
Importantly, while the generation of induced pluripotent stem (iPS) cells may have resolved the problem of immunogenic rejection, the risk of teratoma formation remains a major obstacle that is equally relevant for embryonic stem (ES) cells and for iPS cells [Miura et al., Nature Biotechnology 27:743-745 (2009); Fu et al., Stem Cells and Development 21:521-529 (2012); Ben-David & Benvenisty, Nature Reviews Cancer 11:268-277 (2011); Puri & Nagy, Stem Cells 30:10-14 (2012).
To promote the removal of residual pluripotent cells from differentiated cultures, several strategies have been suggested, based on either genetic manipulations or cell sorting, including: introduction of suicide genes [Schuldiner et al., Stem Cells 21:257-265 (2003); Hara. et al., Stem Cells and Development 17:619-627 (2008)]; interference with tumor progression genes [Blum et al., Nature Biotechnology 27:281-287 (2009)] or with tumor suppressors [Menendez et al., Aging Cell 11:41-50 (2012)]; fluorescence-activated or magnetic-activated cell sorting (FACS or MACS) based on antibodies against PSC-specific surface antigens [Fong et al., Stem Cell Reviews 5:72-80 (2009); Tang et al., Nature Biotechnology 29:829-834 (2011); Wang et al., Cell Research 21:1551-1563 (2011)]; and the use of cytotoxic antibodies against pluripotent cells [Choo et al., Stem Cells 26:1454-1463 (2008); Schriebl et al., Tissue Engineering Part A (2012 Jan. 4, electronically published)].
Previous studies have suggested that hPSCs may be especially sensitive to some cellular perturbations, and are thus more prone than other cell types to undergo apoptosis under some circumstances [Qin et al., Journal of Biological Chemistry 282:5842-5852 (2007); Momcilovic et al., PloS One 5:e13410 (2010)].
The cancer stem cell hypothesis postulates that cancer growth is driven by a subset of cancer cells, referred to in the art as cancer stem cells or cancer stem-like cells (CSCs), which are characterized by tumor-initiation potential, self-renewal capacity, resistance to therapy and an ability to differentiate into heterogeneous and possibly non-tumorigenic cancer cells [Scaffidi & Misteli, Nature Cell Biology 13:1051-1061 (2011); Campos et al., Clinical Cancer Research 16:2715-2728 (2010); Medema, Nature Cell Biology 15:338-344 (2013); Visvader & Lindeman, Nature Reviews Cancer 8:755-768 (2008)]. CSCs which have been reported include a subpopulation of leukemia cells which express CD34 but not CD38 [Bonnet & Dick, Nature Medicine 3: 730-737 (1997], as well as cancer cell subpopulations in brain cancer [Singh et al., Cancer Research 63:5821-5828 (2003)], breast cancer [Al-Hajj et al., PNAS 100:3983-3988 (2003)], colon cancer [O'Brien et al., Nature 445:106-110], ovarian cancer [Zhang et al., Cancer Research 68:4311-4320 (2008)], pancreatic cancer [Li et al., Cancer Research 67:1030-1037 (2007)], prostate cancer [Maitland & Collins, Journal of Clinical Oncology 26:2862-2870 (2008); Lang et al., Journal of Pathology 217:299-306 (2009)], melanoma [Schatton et al., Nature 451:345-349 (2008); Boiko et al., Nature 466:133-137 (2010); Schmidt et al., PNAS 108:2474-2479 (2011); Civenni et al., Cancer Research 71:3098-3109 (2011)] and multiple myeloma [Matsui et al., Blood 103:2332-2336 (2004); Matsui et al., Cancer Research 68:190-197 (2008)].
Stearoyl-CoA desaturase (SCD) is an enzyme which catalyzes production of oleic acid by desaturation of stearic acid. Two isoforms, SCD1 and SCD5, have been reported in humans.
Inhibition of SCD1 has been reported to induce endoplasmic reticulum (ER) stress and unfolded protein response (UPR) in some human cancer cell lines, leading to apoptosis of these cells, and has been suggested as a potential target for cancer therapy [Roongta et al., Molecular Cancer Research 9:1551-1561 (2011); Minville-Walz et al., PloS One 5:e14363 (2010); Scaglia et al., PloS One 4:e6812 (2009); Hess et al., PloS One 5:e11394 (2010); Morgan-Lappe et al., Cancer Research 67:4390-4398 (2007); Mason et al., PloS One 7:e33823 (2012)]. SCD1 has been reported to be expressed in hPSCs [Assou et al., Stem Cells 25:961-973 (2007)], but its role in these cells has not been previously described.
Accumulation of saturated fatty acid SCD1 substrates has been reported to induce ER stress and UPR by several mechanisms: generation of reactive oxygen species (ROS), which leads to ER calcium depletion [Borradaile et al., Molecular Biology of the Cell 17:770-778 (2006)]; alteration of the ER membrane composition, which results in a dramatic impairment of its structure and integrity [Borradaile et al., Journal of Lipid Research 47:2726-2737 (2006)]; and impairment of the ER-to-Golgi trafficking, which results in the build-up of proteins in the ER [Preston et al., Diabetologia 52:2369-2373 (2009)]. Oleic acid, the product of SCD1 activity, has been reported to compete with the saturated fatty acids, block the abnormal lipid distribution, and attenuate ER stress [Peng et al., Endocrinology 152:2206-2218 (2011); Hapala et al., Biology of the Cell/under the auspices of the European Cell Biology Organization 103:271-285 (2011)].
High SCD activity has been reported to be associated with increased cardiovascular risk profile, including elevated plasma triglycerides, high body mass index and reduced plasma HDL [Attie et al., J Lipid Res 43:1899-1907 (2002)].
International Patent Application PCT/CA2006/000949 (published as WO 2006/130986), International Patent Application PCT/CA2007/001026 (published as WO 2007/143823), International Patent Application PCT/CA2007/001027 (published as WO 2007/143824), International Patent Application PCT/CA2007/001396 (published as WO 2008/017161), International Patent Application PCT/CA2007/001858 (published as WO 2008/046226), International Patent Application PCT/CA2007/002139 (published as WO 2008/064474) and U.S. Patent Application No. 2008/0182838 describe SCD1 inhibitors and uses thereof in the treatment of cardiovascular disease, obesity, diabetes, neurological disease, metabolic syndrome, insulin resistance, cancer and liver steatosis.
Additional background art includes Behrouzian and Buist [Prostaglandins, Leukotrienes and Essential Fatty Acids 68:107-112 (2003)]; Raju and Reiser [J Biol Chem 242:379-384 (1967)]; Park et al. [Biochim Biophys Acta 1486:285-292 (2000)]; Liu et al. [J Med Chem 50:3086-3100 (2007)]; Zhao et al. [Bioorg Med Chem Lett 17:3388-3391 (2007)]; Xin et al. [Bioorg Med Chem Lett 18:4298-4302 (2008)]; and International Patent Applications having publication nos. WO 2005/011653, WO 2005/011654, WO 2005/011655, WO 2005/011656, WO 2005/011657, WO 2006/014168, WO 2006/034279, WO 2006/034312, WO 2006/034315, WO 2006/034338, WO 2006/034341, WO 2006/034440, WO 2006/034441, WO 2006/034446, WO 2006/086445, WO 2006/086447, WO 2006/101521, WO 2006/125178, WO 2006/125179, WO 2006/125180, WO 2006/125181, WO 2006/125194, WO 2007/044085, WO 2007/046867, WO 2007/046868, WO 2007/050124, WO 2007/130075, WO 2007/136746, WO 2008/074835, WO 2008/074835, WO 2008/074824, WO 2008/036715, WO 2008/044767, WO 2008/029266, WO 2008/062276, WO 2008/127349, WO 2008/003753, WO 2007/143697, WO 2008/024390, WO 2008/096746 and WO 2008/056687; and Liu [Expert Opinion on Therapeutic Patents 19:1169-1191 (2009)].